title: The peroxisome proliferator-activated receptor α agonist fenofibrate decreases airway reactivity to methacholine and increases endothelial nitric oxide synthase phosphorylation in mouse lung.
abstract: In the present study, we have investigated the effect of the peroxisome proliferator-activated receptor α (PPARα) agonist fenofibrate on airway reactivity and the role of the endothelial nitric oxide synthase (eNOS)/NO pathway in this effect. Airway reactivity to methacholine was assessed in C57BL/6 mice treated or not with fenofibrate by whole-body plethysmography. In some experiments, animals were administered with the NOS inhibitor L-NAME, one hour before airway reactivity measurement. Expression and phosphorylation of eNOS were evaluated in lung homogenates from fenofibrate and control animals using Western blotting. Fenofibrate dose and time dependently decreased airway reactivity to methacholine in mice. A statistically significant (P < 0.05) reduction was observed after a treatment of 10 days with a dose of 3 or 15 mg/day fenofibrate. Mice treated with fenofibrate and administered with l-NAME exhibited similar reactivity to methacholine than vehicle-treated mice administered with the NOS inhibitor, suggesting that NO mediates fenofibrate-induced decrease in airway reactivity. eNOS levels remained unchanged in the lung from mice treated with fenofibrate, but phosphorylation of the enzyme at Ser-1177 was increased by 118% (P < 0.05). Taken together, our data demonstrate that fenofibrate downregulates airway reactivity to methacholine in the mouse and suggest that this effect could involve an increase in NO generation through an enhanced eNOS phosphorylation.
authors.affiliation: EA3771 Inflammation et environnement dans l'asthme, Faculté de Pharmacie, Université Louis Pasteur-Strasbourg I, 74 route du rhin, BP 60024, 67401 Illkirch, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Becker
authors.forename: Carine
authors.initials: C
authors.lastname: Delayre-Orthez
authors.forename: Nelly
authors.initials: N
authors.lastname: Frossard
authors.forename: Françoise
authors.initials: F
authors.lastname: Pons
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D016210:Methacholine Chloride / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D047493:PPAR alpha / Q000819:agonists* / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D047493:PPAR alpha; D016210:Methacholine Chloride; D052250:Nitric Oxide Synthase Type III; D011345:Fenofibrate